Method and apparatus to control conduction through the heart to treat cardiac conditions

ABSTRACT

Control of conduction through a heart is described. A lead with a proximal end and a distal end is provided. The distal end of the lead is inserted into a target area. An agent is delivered through the lead to the target area. Delivery of the agent is monitored via a closed loop feedback system.

RELATED APPLICATION

This application is related to, and claims the benefit of,provisionally-filed U.S. Patent Application Ser. No. 60/464,767 filedApr. 23, 2003, and U.S. patent application Ser. No. 10/798,613 filedMar. 11, 2004 entitled “System for the Delivery of a Biologic Therapywith Device Monitoring and Back-Up”, which are incorporated herein byreference in their entirety. This application is also related to, andclaims the benefit of, provisionally-filed U.S. Patent Application Ser.No. 60/684,658, filed May 26, 2005.

FIELD OF THE INVENTION

The present invention relates generally to cardiovascular therapies and,more particularly, to control of conduction through the heart.

BACKGROUND OF THE INVENTION

Cardiac conditions such as supraventricular arrhythmias (SVA) or chronicheart block are treated with device therapies, drug therapies, or acombination thereof. Device therapies typically involve implantablemedical devices (IMDs). IMDs are effective except with some patientsthat experience SVA or chronic heart block. One such example relates toimplantable pulse generators (IPGs) or implantablecardioverter-defibrillators (ICDs) that deliver electrical stimulationto the vagal nerve plexes located in the heart. Stimulation of vagalnerve plexes enhances parasympathetic input to the atrioventricular (AV)node and subsequently slows AV nodal conduction and ventricular rate.While this therapy operates acutely, tachyphylaxis may occur.Tachyphylaxis is a rapidly decreasing response to a drug orphysiologically active agent after administration of a few doses.Additionally, vagal stimulation may induce atrial arrhythmias.

Combined device and drug therapies are costly. One such therapy relatesto ventricular rate sensors of an IMD that rely on a sensor-basedalgorithm to regulate the delivery of drugs. In this case, drugs aretypically taken orally on a daily basis regardless of the existence ofatrial fibrillation (AF) or inadequate ventricular rate in a heart. Adaily dosage is problematic for some patients. For example, somepatients are excessively bradycardiac while in sinus rhythm andexperience an elevated ventricular rate in AF. To address this problem,a pacemaker is implanted to detect “drug induced brady” conditions andto control the rate of drug delivery. Pacemakers increase patients'costs.

Drug therapies also have drawbacks. Drugs are delivered through systemiccirculation of a patient. Examples of systemic drug delivery includeoral, intravenous, subcutaneous, or transdermal delivery methods. Sincesystemic drug delivery introduces drugs to all organs and tissue,non-targeted organs or tissue may exhibit drug toxicity. Drug toxicityconcerns limit the dosage that is administered to a patient. Limiting adosage may reduce the effectiveness of the drug. Systemic drug deliverymay also cause side effects in the patient, which reduces tolerabilityor effectiveness of drugs. For example, drugs that slow down AV nodalconduction may cause side effects such as sinus bradycardia, congestiveheart failure, fatigue, or constipation.

Some gene therapies claim to chronically transfect AV nodal tissue withspecific genes to control conduction rate through the AV node. However,it is unclear whether these gene therapies adequately control titrationof an agent to achieve therapeutic goals. Consequently, gene therapy mayresult in uncontrollable or inadequate AV nodal rate. It is thereforedesirable to have therapies that overcome the limitations describedabove.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will become more fully understood from thedetailed description and the accompanying drawings, wherein:

FIG. 1 is a block diagram of an exemplary system to control conductionthrough a heart;

FIG. 2 is a partial perspective view of an exemplary medical device thatdelivers therapeutic agent to myocardial tissue of a patient;

FIG. 3 is a flow diagram of a method to detect cardiac conditions;

FIG. 4 is a flow diagram of a method to treat cardiac conditions when apatient has low physical activity;

FIG. 5 is a flow diagram of a method to treat cardiac conditions when apatient has increased physical activity;

FIGS. 6A-6B are flow diagrams of a method to control atrial ventricularconduction time;

FIG. 7 is a flow diagram of a method to detect cardiac conditions;

FIG. 8 is a flow diagram of a method to treat cardiac conditions;

FIG. 9 is a flow diagram of a method to treat cardiac conditions basedupon patient activity;

FIG. 10A is a bar diagram in which ventricular rate is controlled;

FIG. 10B is a electrocardiogram in which ventricular rate is controlled;

FIG. 10C is a block diagram of FIG. 10B in which ventricular rate iscontrolled; and

FIG. 10D is a bar diagram of reversible increase of AH and AV intervalsduring continuous administration of an agent.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The following description of embodiments is merely exemplary in natureand is in no way intended to limit the invention, its application, oruses. For purposes of clarity, similar reference numbers are used in thedrawings to identify similar elements.

The present invention is directed to control of conduction through aheart. This is accomplished, in part, by monitoring delivery of an agent(e.g. drug, biologic, drug/biologic, etc.) to a target area through aclosed loop feedback system. Closed loop feedback systems typicallyrelate to implantable medical devices (IMDs). An IMD includes a firstand a second lead. The distal end of the first lead is inserted into oraround the target area (e.g. atrialventricular (AV) nodal area etc.).The first lead then delivers the agent to the target area. The IMDmonitors the electrical response from the heart by accessing data via anelectrode at a distal end of a second lead. Adjustments are made to theamount of agent delivered based upon the sensed electrical response fromthe heart by accessing data. In this manner, a patient's ventricularrate is maintained at an optimal level.

A variety of cardiovascular conditions are treated through control of AVconduction time. For example, the present invention treats paroxysmalchronic supraventricular arrhythmias (i.e. atrial fibrillation, atrialflutter, atrial tachycardia, supraventricular tachycardia).Additionally, chronic heart block (i.e. chronic atrial fibrillation (AF)conditions, chronic AV block conditions) is also treated through thecontrol of the ventricular rate or atrialventricular conduction time.Episodic periods of AF with fast ventricular response are also managed.Furthermore, the present invention improves the treatment and managementof atrial bradyarrhythmias.

The present invention also improves treatment of cardiovascularconditions. For example, drug dosages are reduced by five to twentyfold. Additionally, low or undetectable systemic plasma concentrationsare obtained. Elimination or diminution is achieved for non-cardiac andcardiac side effects (e.g. ventricular proarrhythmia etc.). Non-orallybioavailable drugs can be administered. Greater efficacy or duration ofaction is obtained. Episodic drug delivery decreases the risk for drugtoxicity and complication. Episodic delivery also increases the timeperiods between drug replacement in the implantable drug deliveryarrhythmia management system. A synergistic effect may be obtained incombination with electrical stimulation therapies.

FIG. 1 depicts a block diagram of system 10 that treats cardiacconditions (e.g. supraventricular arrhythmias, chronic heart block etc.)by monitoring the effectiveness of an agent delivered to myocardialtissue. System 10 includes IMD 12, one or more leads 20 a-20 c, andagent reservoir 30. A detailed example of an IMD 12 may be seen withrespect to a U.S. patent application Ser. No. 10/465,351 filed on Jun.19, 2003, and assigned to the assignee of the present invention, thedisclosure, in relevant part, is incorporated by reference. ExemplaryIMDs 12 include an IPG to provide a pacing function, an ICD to provideshocks, a monitoring implant to record various cardiac performancecharacteristics, or a device that combines these functions.

Leads 20 a-20 c, which extend from IMD 12, are inserted into or aroundthe myocardial tissue. For example, distal end of lead 20 a is in theright atrium, distal end of lead 20 b is in the right ventricle, anddistal end of lead 20 c is in or in close proximity to the AV node.Leads 20 a-20 c include electrodes to sense data related tocardiovascular variables or parameters. Lead 20 c also includes adelivery line (not shown) that allows delivery of the agent to themyocardial tissue. An agent delivery system 30, coupled to lead 20 c viaconductive line 21, contains and pumps the desired agent (e.g. drug,biologic agent, drug/biologic agent, genetic material etc.) to themyocardial tissue. Line 21 is a coaxial line that includes a conductiveline (e.g. wire) and an agent delivery line (not shown).

An exemplary catheter 18 to deliver therapeutic agent to tissue isdepicted in FIG. 2. Catheter 18 includes a catheter body 19, lead 20 cand a fluid container 50. Lead 20 c comprises a lead body 22, one ormore electrodes 24, and an anchoring mechanism 34. Lead body 22 has aproximal end 35, a distal end 36, and a lumen therebetween. Anchoringmechanism 34 (e.g. a fixed screw etc.), disposed near distal tip 25 oflead 20 c, is configured to secure lead 20 c to the myocardial tissue(e.g. AV nodal tissue etc.). Ideally, lead 20 c is affixed in or aroundthe triangle of Koch of the myocardial tissue. Fluid container 50interconnects agent delivery system 30 with the myocardial tissue. Fluidcontainer 50 is guided through lead 20 c and is either removed after theprocedure or left in place. Distal tip 55 of fluid container 50 eithercontacts the myocardial tissue or is forced into the myocardial tissue.

System 10 operates as a closed loop feedback system. For example, IMD 12signals agent delivery system 30 over line 21 to deliver an agent tomyocardial tissue. Exemplary agents include calcium channel antagonists,beta-adrenergic antagonists, digitalis-derived drugs, purinergic agents(e.g. adenosine compound, etc.), parasympathetic agents, (e.g.acetylcholine-like compounds, etc.), local anesthetics, adrenergicagonists or other suitable material. In response to signals from IMD 12,agent delivery system 30 pumps agent via a pump (not shown) through lead20 c. The agent is delivered through the fluid container 50 and into oronto the myocardial tissue. The agent regulates AV nodal conduction. Forexample, the agent controls the speed at which a depolarizationwavefront passes from the atrium to the ventricule. In the case ofsupraventricular tachycardias (SVT), the speed of the depolarizationwavefront is decreased. In contrast, the speed of the depolarizationwavefront is increased for AV nodal block. Sensed data is thentransmitted over one or more leads 20 a-20 c via their respectiveelectrodes 24 to IMD 12. Based upon the sensed data, IMD 12 thendetermines whether an adjustment of the agent dosage is required. If anadjustment is required, IMD 12 signals agent delivery system 30 toincrease, decrease, or stop agent delivery.

FIGS. 3 through 6A-6B generally depict an embodiment to monitor theeffect of an agent on myocardial tissue and then, if necessary, adjustthe agent dosage. These operations are embodied in computer instructionsthat are stored in memory (e.g. RAM) and executed on the microprocessorof IMD 12. FIG. 3 specifically relates to monitoring for cardiacconditions. At operation 100, a patient's heart rate is sensed throughthe electrode(s) of one or more leads 20 a-20 c. At block 110, adetermination is made as to whether an arrhythmia is occurring. Ifarrhythmia is not detected, system 10 continues to sense data related tothe heart rate at block 100. Alternatively, if an arrhythmia isdetected, the ventricular rate is sensed by one or more of electrodes ofleads 20 a-20 c at block 120. At block 130, a determination is made asto whether an elevated ventricular response is occurring. An undetectedelevated ventricular response causes system 10 to return to block 120 tocontinue to sense data related to ventricular rate. If an elevatedventricular response is detected, the patient's level of activity issensed at block 140. At block 150, a determination is made as to whetherthe patient is at rest. If the patient is at rest, the operation goes toblock 300 of FIG. 5. In contrast, if the patient is at rest, theoperation goes to block 200 of FIG. 4.

FIG. 4 is a flow diagram depicting a method to treat a patient forcardiovascaular conditions while in an inactive physical state (i.e.rest state). Generally, blocks 300-340 relate to treatment of a highventricular rate; blocks 350-380 relate to maintaining a desirableventricular rate; and blocks 410-480 relate to treatment of a lowventricular rate. At block 300, agent delivery to a target area (e.g. AVnodal area, etc.) occurs. At block 310, a determination is made as towhether a high ventricular rate is occurring. Typically, a highventricular rate is greater than 80 beats per minute (BPM). However,age, pre-existing disease, pre-existing physiological sinus heart rate(if available) and other factors are considered by the physician whenprogramming the ventricular heart rate levels. If high ventricular ratedata is sensed from the electrical activity of the myocardial tissue,IMD 12 signals agent delivery system 30 to increase the agent dosagelevel at block 320. The elevated dosage level is also referred to as afirst dosage level. A determination is then made as to whether theventricular rate is within the desired range after the administration ofthe first dosage level at block 330. A desired ventricular rate range istypically greater than 60 BPM and less than 80 BPM. If the ventricularrate is not within the desired range after a certain time period, theagent is administered at another elevated dosage level at block 320. Forexample, if the ventricular rate exceeds 100 bpm for over 5 minutes atrest while a drug is administered at a given dosage X, then dosage X isincreased 10-200% until the ventricular rate is within the desiredrange. Alternatively, if the ventricular rate is determined to be withinthe desired range, delivery of the agent in its current dosage iscontinued at block 340.

If it is determined that a high ventricular rate does not exist at block310, the operation turns to maintenance of a desired ventricular rate. Adetermination is made as to whether the ventricular rate is within adesired range at block 350. If the ventricular rate is below the desiredventricular rate, delivery of the agent is stopped at block 400. If theventricular rate is within the desired range, the agent is continuouslydelivered in its current dosage at block 360. A determination is thenmade as to whether the arrhythmia has stopped at block 370. If thearrhythmia has ceased, the agent is continuously delivered at itscurrent dosage to the target area at block 300. If not, a determinationis made as to whether the heart rate is too low at block 375. If theheart rate is not too low, delivery of the agent is stopped at block 380and system 10 returns to monitoring cardiovascular conditions at block100 of FIG. 3. If the heart rate is too low, a pacing operation isimplemented at operation 420.

Blocks 400-480 generally relate to treatment of a low ventricular rate.At block 400, delivery of the agent is stopped for low range ventricularrate (e.g. typically less than 60 BPM). At block 410, a determination ismade as to whether pacing is required. If pacing is required, pacing isperformed at block 420 by one of the leads 20 a-20 c. At block 430, theheart rate is monitored. At block 450, a determination is made as towhether the heart rate is too low. If the heart rate is too low, theoperation makes a determination as to whether pacing is required atblock 410. If the heart rate is not too low, a determination is made asto whether the heart rate is too high at block 460. If the heart rate istoo high, the operation goes to block 310 to determine whether a highventricular rate exists. If the heart rate is not too high, the agent isadministered at a certain dosage level at block 470. For example, if theheart rate is at 160 bpm during exercise, then the AVN blocker drug suchas calcium channel blocker agent (e.g. verapamil etc.) is continuouslydelivered. A determination is then made at block 480 as to whether thearrhythmia has stopped. If the arrhythmia has stopped, delivery of theagent is stopped at block 380. If the arrhythmia has not stopped, theagent is delivered at a certain dosage level at block 470. This dosagelevel is referred to as a second dosage level.

FIG. 5 is a flow diagram that depicts treatment of a cardiac conditionbased upon the activity of a patient instead of ventricular rate. Atblock 500, agent delivery to a target area (e.g. AV nodal area, etc.)occurs. At block 505, a determination is made as to whether a patientexhibits high physical activity. U.S. patent application Ser. No.10/465,351, incorporated by reference, in relevant part, brieflydescribes sensors for activity.

Typically, high physical activity is determined by increased activity ofthese sensors (e.g. motion sensor, etc). If high physical activity datais sensed from the electrical activity of the myocardial tissue, IMD 12signals agent delivery system 30 to increase the agent dosage level atblock 510. The elevated dosage level is also referred to as a firstdosage level. A determination is then made as to whether the patient,who is experiencing high physical activity, nevertheless maintains theheart beat within a desired range after the administration of the firstdosage level at block 515. If the heart rate is not within the desiredrange within a certain time period, the agent is administered at anotherelevated dosage level at block 510. For example, the patient has aventricular rate of 180 bpm at a given dosage level X, then this dosagelevel is increased by 10-200%. Alternatively, if the heart rate isdetermined to be within the desired range, delivery of the agent in itscurrent dosage is continued at block 520.

If it is determined that a high physical activity does not exist atblock 505, the operation turns to medium level of physical activityoperations. A determination is made as to whether medium physicalactivity is occurring at block 525. If the ventricular rate is below thedesired ventricular rate, delivery of the agent is stopped at block 550.If medium physical activity is occurring, the agent is continuouslydelivered in its current dosage at block 530. A determination is thenmade as to whether the arrhythmia has stopped at block 535. If thearrhythmia has ceased, the agent is continuously delivered at itscurrent dosage to the target area at block 500. If not, a determinationis made as to whether the heart rate is too low at block 540. If theheart rate is not too low, delivery of the agent is stopped at block 545and the system returns to monitoring cardiovascular conditions at block100 of FIG. 3.

Blocks 550-585 generally relate to treatment of a patient during lowphysical activity. At block 550, delivery of the agent is stopped forlow range ventricular rate (e.g. less than 60 BPM). At block 555, adetermination is made as to whether pacing is required. If pacing isrequired, pacing is performed at block 560 by one of the leads 20 a-20c. At block 565, the heart rate is monitored. At block 570, adetermination is made as to whether the heart rate is too low. If theheart rate is too low, the operation makes a determination as to whetherpacing is required at block 555. If the heart rate is not too low, adetermination is made as to whether the heart rate is too high at block575. If the heart rate is too high, the operation goes to block 505 todetermine whether a high physical activity exists. If the heart rate isnot too high, the agent is administered at a certain dosage level atblock 580. For example, a calcium blocking agent may be delivered if theventricular heart rate is 160 beats per minute. A determination is thenmade at block 585 as to whether the arrhythmia has stopped. If thearrhythmia has stopped, delivery of the agent is stopped at block 545.If the arrhythmia has not stopped, the agent is delivered at a certaindosage level at block 580. This dosage level is referred to as a seconddosage level.

FIGS. 6A and 6B depict operations to control AV conduction time. Atblock 700, the heart rate is sensed by system 10. At block 710, AVconduction time is monitored. At block 720, a determination is made asto whether AV conduction time too high. If AV conduction time is not toohigh, the operation loops back to block 710 to monitor AV conductiontime. Alternatively, if AV conduction time is too high, agent isdelivered to the target area at block 730. At block 740, a determinationis made as to whether AV conduction time is lower than 100 microseconds.If AV conduction time is not lower than 100 milliseconds) (ms), adetermination is then made at block 780 as to whether AV conduction timeis less than 250 ms. In contrast, if AV conduction time is lower than100 ms, agent delivery is stopped at block 750. At block 760, AVconduction time is monitored. At block 770, a determination is made asto whether AV conduction time is greater than 100 ms. If AV conductiontime is not greater than 100 ms, system 10 loops back to block 760 tomonitor AV conduction time. Alternatively, if AV conduction time isgreater than 100 ms, the agent is delivered to the target area at block730.

Turning now to block 780, a determination is made as to whether AVconduction time is less than 250 ms. If AV conduction time is less than250 ms, delivery of the agent continues at its current dosage at block790.

At block 810, a determination is made as to whether AV block III isoccurring in the patient. If it is not present, agent delivery continuesat a specified dosage at block 820. The heart rate is monitored andappropriate action is taken if a cardiac condition is detected at block825. Optionally, control of system 10 returns to block 700. In contrast,if AV block III is occurring, a determination is made as to whetherpacing is required at block 830. If pacing is required, a pacingoperation is implemented at block 840. The patient's heart rate ismonitored at block 850. A determination is made as to whether the heartrate is too low at block 860. At block 865, the heart rate is monitoredand appropriate action is taken if a cardiac condition is detected.Optionally, control of system 10 returns to block 700.

FIGS. 7-9 illustrate another embodiment to control conduction through aheart. FIG. 7 depicts operations that determine whether a therapeuticalgorithm or a pacing algorithm are implemented. At block 900, the heartrate of a patient is sensed. At block 910, a determination is made as towhether atrial arrhythmia is detected. If no atrial arrhythmia isdetected, any therapy is stopped at operation 915 and the system returnsto sensing the heart rate at block 900. If atrial arrhythmia isdetected, the patient's level of activity is sensed at block 920. Atblock 930, the heart rate is determined. At operation 940, adetermination is made as to whether an elevated ventricular response ispresent. If so, the therapeutic algorithm is implemented at operation950 and the operations in FIG. 8 are then followed. If an elevatedventricular response is not detected, a determination is made as towhether a low ventricular response is present at block 960. If so, astandard pacing algorithm is implemented at operation 970 and theoperations of FIG. 9 are implemented. However, if a low ventricularresponse is not detected, control of the algorithm returns to the startoperation.

FIG. 8 is a flow diagram related to administration of a therapeuticagent taking into consideration a patient's level of physical activity.At operation 1000, an agent is delivered to the target area (e.g.triangle of Koch area). At operation 1010, a determination is made as towhether a condition is satisfied. Exemplary conditions include theelapsed time from which the agent was delivered to the target area,variables related to AF, slope of heart rate change, or other suitableconditions. If the condition is not satisfied, control of the operationreturns to block 1000 in which the agent continues delivery. Incontrast, if the condition is satisfied, the patient's level of activityis checked at block 1015. A determination is then made as to whether alow heart range is present at block 1020. If a low heart range ispresent, a determination is made as to whether a minimum dosage level isbeing applied to patient at block 1030. If the minimum dosage level isbeing used, delivery of the agent at target area is stopped at block1040 and control of the algorithm returns to block 100. In contrast, ifa minimum dosage level is not present, the agent dosage is decreased atoperation 1032 to control of system 10 then turns to block 1000.

If a low heart range is not present in the patient, a determination isthen made at block 1022 as whether a normal heart range is present. Ifthe normal heart range is occurring, agent dosage is maintained at block1024 and control of system 10 returns to block 1000. If a normal heartrange is not present in the patient, a determination is made as towhether the patient is being administered at maximum agent dosage levelat block 1028. If not, agent dosage is increased at block 1029 andcontrol of system 10 returns to block 1000. In comparison, if thepatient is at the maximum dosage level, a patient alert is sent to thephysician at block 1026 and control of the algorithm returns to block1000 at operation 1049.

FIG. 9 relates to checking patient's level of activity. At operation1100, the heart rate of the patient is sensed. At block 1110, adetermination is made as to whether atrial arrhythmia is occurring. Ifnot, any applicable therapy is stopped at block 1115 and control ofsystem 10 returns to sensing the heart rate at 1100. If atrialarrhythmia is detected, the patient's level of activity is sensed usingan activity sensor at block 1120. A determination is made as to thepatient's heart rate at block 1130. At block 1140, a determination ismade as to whether an elevated ventricular response is present. At block1150, if there is an elevated ventricular response, control of thealgorithm returns to block 1020. In contrast, if an elevated ventricularresponse is not present, a determination is made as to whether a lowventricular response is occurring in the patient at block 1060. Astandard pacing algorithm is implemented at block 1170 if a lowventricular response is present. In contrast, if the patient lacks a lowventricular response, control of the operation returns to the start ofthe algorithm.

FIGS. 10A-10D represent in vivo experimental data obtained fromanesthetized animals based upon features of the claimed invention.Specifically, this data demonstrates that local drug delivery directlyinto the AVN region effectively controls ventricular rate during AFwithout producing systemic effects and toxicity. This study evaluatedthe effect of locally administered acetylcholine (ACH) on AVN conductionand refractoriness properties during sinus rhythm and AF. Canines (n=7)were anesthetized, and instrumented to assess atrial and ventricularelectrophysiology as well as arterial blood pressure. A custom drugdelivery catheter was fixed into the AVN region using a combination ofstandard electrophysiological mapping techniques and image guidedtherapy via a cardiac navigation system. Its location was confirmed bydelivering an ACH test dose and resultant complete, but fully reversibleheart block in all 7 animals. As noted from data presented below inTable 1, the duration of AV block administered via direct AVN injectionwas substantially longer than for intravenous administration of theidentical dose.

TABLE 1 AV Block III duration and overall AV Block duration for directAVN Bolus injection vs. Intravenous Bolus injection. Direct AVN BolusIntravenous Bolus (n = 6) (n = 5) Overall AV Block duration* (min) 41.19± 27.14 0.31 ± 0.43 AV Block III duration (min) 12.30 ± 4.72 0.00 ± 0.00*Duration of AV block I, II and III

Subsequently, incremental doses of ACH starting at 10 ug/min wereinfused into the AVN until complete atrioventricular heart block (AVB)was observed. ACH produced AVB in a dose dependent manner. Duringelectrically induced AF, the ventricular rates decreased from 182±32 to77±28 beats per minutes (bpm) (acetylcholine dosage inducing firstdegree AVB; p<0.05) and to 28±8 bpm (third degree AVB; p<0.05) (FIG.10A). Raw data obtained during electrically induced AF are shown in FIG.10B during and without drug administration. At the first degree AVBdose, AVN effective refractory period (ERP) at a pacing cycle length of400 milliseconds (msec) increased from 186±37 msec to 282±33 msec(p=0.06), and Wenckebach cycle length from 271±29 msec to 378±58 msec(p<0.05) (FIG. 10C). In addition, ACH dose producing first AVB prolongedAV, PR and AH intervals, whereas PP intervals, HV intervals and bloodpressure remained unchanged, demonstrating a local effect (FIG. 10D).Observed effects were fully reversible within 20 minutes after stoppingACH infusion. From this in vivo data, local ACH delivery into the AVNregion successfully increased AVN refractoriness and significantlydecreased ventricular rate response during electrically induced AF in adose related fashion. These effects occurred without significantsystemic effects and were rapidly reversible within minutes. This mayrepresent a novel drug delivery therapy whereby direct AVN drug deliveryis monitored and controlled to maintain an optimal ventricular rateduring AF events.

The present invention has numerous applications. For example, while thefigures relate to AF, other types of cardiac conditions may be treatedby this process. For example, AV block may rely on the embodimentpresented in FIGS. 7-9. To illustrate, blocks 1020 and 1028 may beswitched with each other. Additionally, the blocks that describe “atrialarrhythmia” are switched to AV block. The rest of the blocks remainunchanged. The description of the invention is merely exemplary innature and, thus, variations that do not depart from the gist of theinvention are intended to be within the scope of the invention. Suchvariations are not to be regarded as a departure from the spirit andscope of the invention.

1-21. (canceled)
 22. A method of treating atrial fibrillation in apatient, the method comprising: delivering a therapeutic agent directlyinto AV nodal tissue of the patient in response to a determination ofatrial fibrillation to decrease ventricular rate; monitoring anelectrical response by the heart to the delivered therapeutic agent viaa closed loop system, wherein monitoring the electrical responsecomprises monitoring AV conduction time; and adjusting a quantity of thetherapeutic agent delivered directly to the AV nodal tissue using theclosed loop system until a preferred AV conduction time is attained. 23.The method of claim 22, further comprising: determining whether AVconduction time is greater than 100 ms; determining whether AVconduction time is less than 250 ms; and continuing to deliver thetherapeutic agent directly into AV nodal tissue until preferred AVconduction time is attained if the AV conduction time is greater than100 ms and less than 250 ms.
 24. The method of claim 22, furthercomprising: determining whether AV conduction time is less than 100 ms;and ceasing delivery of the therapeutic agent in response to determiningAV conduction time is less than 100 ms.
 25. The method of claim 24,further comprising: continuing to monitor AV conduction time uponceasing delivery of the therapeutic agent in response to determining AVconduction time is less than 100 ms; and delivering therapeutic agentdirectly into AV nodal tissue if AV conduction time becomes greater than100 ms after delivery was previously ceased.
 26. The method of claim 22,further comprising: determining whether AV conduction time is greaterthan 250 ms; and determining whether AV block III is present in thepatient in response to determining AV conduction time is greater than250 ms.
 27. The method of claim 26, further comprising determining ifpacing is required in response to determining that AV block III ispresent.
 28. The method of claim 26, further comprising delivering aquantity of therapeutic agent different than previously being deliveredif AV block III is not determined when AV conduction time is greaterthan 250 ms.
 29. The method of claim 22, further comprising: determiningwhether AV conduction time is less than 250 ms; and delivering thetherapeutic agent directly into AV nodal tissue until a preferred AVconduction time is attained if AV conduction time is less than 250 ms.30. The method of claim 22, further comprising: determining whether AVconduction time is greater than 100 ms; and delivering the therapeuticagent directly into AV nodal tissue until a preferred AV conduction timeis attained if AV conduction time is greater than 100 ms.
 31. The methodof claim 22, further comprising: determining whether AV conduction timeis greater than 100 ms; and determining whether AV conduction time isgreater than 250 ms in response to determining AV conduction time isgreater than 100 ms.
 32. A method of treating atrial fibrillation in apatient, the method comprising: delivering a therapeutic agent directlyinto AV nodal tissue of the patient; monitoring an electrical responseby the heart to the delivered therapeutic agent via a closed loopsystem, wherein monitoring the electrical response comprises monitoringAV conduction time of the heart; adjusting a quantity of the therapeuticagent delivered to the AV nodal tissue using the closed loop systemuntil a preferred AV conduction time is attained if AV conduction timeis greater than a lower AV conduction time and less than an upper AVconduction time; ceasing delivery of the therapeutic agent in responseto determining AV conduction time is less than the lower AV conductiontime; and determining whether a cardiac condition requiring pacing ispresent if the AV conduction is greater than the upper AV conductiontime.
 33. The method of claim 32, wherein the lower AV conduction timeis 100 ms and the upper AV conduction time is 250 ms.
 34. The method ofclaim 32, wherein ceasing delivery of the therapeutic agent in responseto determining AV conduction time is less that the lower AV conductiontime comprises ceasing delivery of the therapeutic agent in response todetermining AV conduction time is less than 100 ms.
 35. The method ofclaim 32, further comprising: continuing to monitor AV conduction timeupon ceasing delivery of the therapeutic agent upon determining AVconduction time is less than the lower AV conduction time; anddelivering therapeutic agent directly into AV nodal tissue if AVconduction time becomes greater than the lower AV conduction time afterdelivery was previously ceased.
 36. The method of claim 32, whereindetermining whether a cardiac condition requiring pacing is present ifthe AV conduction is greater than the upper AV conduction time comprisesdetermining whether AV block III is present in the patient in responseto determining AV conduction time is greater than the upper AVconduction time,
 37. The method of claim 36, further comprisingdetermining if pacing is required in response to determination that AVblock III is present.
 38. The method of claim 36, further comprisingdelivering a quantity of therapeutic agent different than previouslybeing delivered if AV block III is not determined when AV conductiontime is greater than the upper AV conduction time.
 39. The method ofclaim 32, wherein adjusting a quantity of the therapeutic agentdelivered to the AV nodal tissue using the closed loop system comprises:determining whether AV conduction time is less than 250 ms; anddelivering the therapeutic agent directly into AV nodal tissue until apreferred AV conduction time is attained if AV conduction time is lessthan 250 ms.
 40. The method of claim 32, wherein adjusting a quantity ofthe therapeutic agent delivered to the AV nodal tissue using the closedloop system comprises: determining whether AV conduction time is greaterthan 100 ms; and delivering the therapeutic agent directly into AV nodaltissue until a preferred AV conduction time is attained if AV conductiontime is greater than 100 ms.
 41. The method of claim 32, whereinmonitoring AV conduction time comprises: determining whether AVconduction time is greater than 100 ms; and determining whether AVconduction time is greater than 250 ms in response to determining AVconduction time is greater than 100 ms.